The present invention is broadly directed to a method for inducing endothelium dependent vasodilation, smooth muscle relaxation, especially such events associated with sexual functions, e.g., penile erection, clitoral engorgement and erection. The present invention is particularly directed to the use of a particular class of isozyme selective Protein Kinase C (PKC) inhibitors for treating sexual dysfunctions, e.g., impotence in diabetic men and arousal and orgasm disorders in women.
2. Description of Related Art
The prevalence of impotence in diabetic men has been reported to be as high as 50 percent. The neurologic and vascular complications of diabetes are presumed to be responsible for the associated erectile dysfunction. Studies in animal models of diabetes. as well as in humans, have uncovered pathologic changes in penile arteries, morphologic alterations of autonomic nerves, and a depletion of neurotransmitters within the corpus cavernosum.
Vasodilation and relaxation of the smooth muscle of the corpus cavernosum lead to penile erection. Dilation of the arterioles that perfuse the lacunar spaces and relaxation of the corporal smooth muscle that surrounds these spaces result in the engorgement of the corporal bodies with blood. The expansion of the lacunar spaces against the tunica albuginea, which encloses the corpora, causes the compression of subtunical venules, restricts blood outflow, and leads to an increase in intracavernosal pressure to a value approximating the mean systemic arterial blood pressure. Thus, it is thought that the impairment of the mechanisms of vasodilation and relaxation of corporal smooth muscle may result in impotence.
The relaxation of penile corporal smooth muscle is controlled locally by nerves that release cholinergic and nonadrenergic, nonocholinergic neurotransmitters; as well as by the vascular endothelium, which lines the lacunar spaces and releases endothelium-derived relaxing factor. Sympathetic nerves cause the contraction of penile corporal smooth muscle by alpha-adrenergic mechanisms and mediate the detumescence of the erect penis.
Medical therapy with androgens offers little more than placebo benefit except in hypogonadal men. Surgical therapy may be useful in the treatment of decreased potency related to aortic obstruction; however, potency can be lost rather than improved after aortic operation if the autonomic nerve supply to the penis is damaged inadvertently. This complication can be minimized if an endarterectomy is done or, in a grafting procedure, if the reconstruction of the distal end is performed above the origin of the external iliac arteries. Early surgical relief of priapism by shunting procedures, such as corpora spongiosum shunting might prevent subsequent impotence.
Another surgical therapy for improvement of potency in refractory patients such as individuals with diabetic neuropathy is the implantation of a penile prosthesis, namely the insertion within the corpora of a small, blunt silastic rod. However, full erection is not produced and the device only prevents buckling during intercourse. Furthermore, the complication rate is high in some series. Alternatively, an inflatable prosthetic device has been devised for implantation on either side of the corpora. A connecting reservoir of material then is placed in the perivesicular space and pumps are located in the scrotum. By means of these pumps the penis can be made to become nearly fully erect at the appropriate time and to relax after intercourse.
As one can appreciate, the presently available treatment for impotence, especially impotence in diabetic men, is not fully satisfactory. There remains a need in the art to develop improved ways to treat impotence, especially impotence in diabetic men.
Sexual functions in females can be divided into several broad areas: desire, arousal, and orgasm. Studies have indicated that up to 63% of women exhibit dysfunctions in either arousal or orgasmic stages of sexual activities (Frank E, et al., 1978. N Engl J Med 299: 111). Sexual disorders such as dyspareunia and vaginismus, reduce the arousal phase of female sexual functioning. Impaired clitoral responsiveness can lead to orgasmic disorders. The prevalence of female sexual dysfunction increases with age (Goldstein M and Teng N. 1991. Clin Geriatr Med 7:41; Thirlaway K et al., 1996. Quality of Life Res 5:81; Slob A et al., 1990. J Sex Martial Ther 16:59). Vascular risk factors of coronary diseases also increase the probability of sexual dysfunction in postmenopausal females (Sadeghi-Nejad H et al., 1996. J Urol 155:677A).
Female sexual dysfunction can be due to an impairment in endothelium dependent vasodilation and smooth muscle relaxation which in turn could lead to impairment of vascular dependent events associated with sexual functioning. During sexual arousal, an increase in vaginal blood flow occurs which in turn results in vaginal lengthening and enhanced production of vaginal fluid. Enhanced clitoral blood flow occurs during arousal leading to clitoral engorgement and erection. Impairment of these vascular dependent events can lead to impairment in vaginal lubrication and/or a diminution in vaginal enlargement during the arousal stage of female sexual function. An abnormality in these vascular dependent events could impair the arousal and/or orgasmic phases of sexual functioning.
A preclinical model of atherosclerosis in New Zealand female rabbits has demonstrated that atherosclerotic lesions reduce pelvic nerve stimulated vaginal engorgement and clitoral erection (Park K et al., 1997. Int J Impot Res 9:27). Thus, pharmacologic agents that prevent or reverse the vascular dysfunction associated with endothelial cell dysfunction, e.g., atherosclerosis might improve vaginal and clitoral responses to sexual arousal. Such therapeutical compounds could in turn lead to a decrease in sexual dysfunction associated with the arousal and orgasmic phases of sexual functioning. In addition, in females who have a coexistent reduction in desire, the alleviation of abnormalities in the arousal and orgasmic phases of sexual functioning could enhance the desire to engage in sexual activity.